In applying for the VA Career Development Award (CDA), I hope to acquire the experience, skills, and knowledge necessary to become an independent faculty investigator who uses patient-driven research to better understand the obstacles to eradication of HIV. My research background includes: 1) investigating the transcriptional control of the proto-oncogene c-kit;2) investigating whether the viral transcription factor Tat contributes to latent infection with HIV-1;and 3) investigating HIV levels and immune parameters within different parts of the gut. This CDA will enable me to obtain additional training in several key areas that will facilitate my transition to an independent translational researcher. Specific areas of training include advanced immunology and virology, biostatistics, design and implementation of clinical studies, scientific collaborations, new laboratory techniques, novel assays, and grant writing. The research environment will include the San Francisco VA Medical Center along with the University of California, San Francisco (UCSF) and its affiliated institutions, including San Francisco General Hospital and the Gladstone Institute. These institutions are nationally known for clinical care, training, and research in HIV. This study seeks to improve understanding of how and why HIV persists on antiretroviral therapy by investigating whether the gut is a site of ongoing replication, whether it is a major reservoir of latently-infected CD4+ T cells (or other cellular reservoirs), and how these cells are maintained. The specific aims are: 1) to quantify levels of HIV (DNA, RNA) in different cell populations and subpopulations in both the gut and peripheral blood;2) to assess for ongoing replication in the ileum by testing for markers that are associated with recent infection;3) to measure the proportion of each gut cell type with inducible, replication-competent, and/or "latent" HIV;4) to investigate mechanisms of latency in the gut;and 5) to evaluate the ability of different anti-latency therapies to reactivate HIV from gut cells and tissues. Gut tissue will be obtained primarily via colonoscopic biopsies of the ileum and rectum. In addition, the study will make use of unused tissue from patients who are undergoing abdominal surgery for clinical reasons unrelated to the study. These biopsies and tissues will be used to identify the cell populations with the most HIV DNA and RNA, to measure inducible and/or replication-competent HIV in the gut, to investigate mechanisms of latency in the gut, and to test the effect of different anti-latency therapies. The knowledge thus gained may ultimately contribute to new and improved therapies aimed at eradication or lifelong coexistence with HIV. PUBLIC HEALTH RELEVANCE: Over 22,000 U.S. veterans with HIV currently receive care through VA facilities, making the VA the largest provider of medical care to HIV+ patients in the U.S. Though antiviral medicines have revolutionized the lives of those with HIV, these therapies are expensive, require lifelong administration and monitoring, cause side effects and toxicities, do not prevent ongoing damage from HIV (average loss of 11 years of life), and are difficult to provide to everybody with HIV. Thus, it seems imperative to explore new and different therapies for HIV, especially those that can possibly lead to eradication. This study seeks to further define and quantify the largest known reservoir of HIV (in the gut), to explore mechanisms that may allow HIV to persist on antiviral therapy (including latent infection and ongoing replication in the gut), and to evaluate therapies aimed at overcoming latent infection in the gut or blood. In doing so, it has the potential to lead to new and improved therapies for HIV, which would have an enormous impact on all HIV+ patients, including U.S. veterans.